Process of preparing purified chlortetracycline hydrochloride



a r v Umted States PatentO ce 2,992,274 Patented July 11, 1961 2 992 274 PROCESS OF PREPARIfiIG PURIFIED CHLOR- Numerical Value I ll J i g w f FQ i Q t 2 to 5.9 1. Suitable for use in any product. v o Q emar, ear ver! v asslgnor o 5 6 to 9 II. Suitable for use in all products except those for,

American Cyanamrd Company, New York, N.Y., a intravenous or topicaluse. corporation of Maine 9-1t0 12 III. Unsatisfactory.

No Drawing. Filed May 4, 1959, Ser. No. 810,593 r 1 Clailll- 260-559) It is important that good and bad standards show fairly typical reactions, although some variation in sensi- T lnvfmtlon relates to lmproved P of tivity of rabbits may aifect this picture slightly. The im Parmg Punfied Chlortetracychne hydrochlonde and more portant factor in reading the test is that the difference Particularly is concerned With an improved Process of between the good and bad reactions must be marked recrystallizing chlortetracycline so as to produce an im-. so that the intermediate reactions may he Propel-1y proved product for use in topical ointments. eva1uated P of the best Procedures for Purifying chlortstra' 15 It has been found that for some unknown reason chlorcycline is disclosed in the United States patent to Wintertetracycline hydrochloride prepared by the Winterhettem bottom F e 1 The Process s s et al. process does not consistently pass this test with a closed involves dissolving crude chlortetracyclrne 1n a rating f IL which would be suitable f use in most Prodhydroxylated Organic solvent by the use of a nitrogenous ucts although parenteral use and use in mastitis ointments base, filtering oil the insoluble impurities, and precipitatrequire a class I rating In many instances i has been ing chlortetracycline hydrochloride therefrom by the adf d necessary to Subject this product to f the ifi a. dltlon of a hydr0ch10r1c ac1d- Thls Process results 111 a tion steps in order to produce products which are satisfacpharmaceutlcal grade of chlortetracycline hydrochloride tory for use in topical Ointmehta -97% Pure which is suitable for Parenter a1 administra' In accordance with the present invention it has been tlon' 25 discovered that by crystallizing the chlortetracycline hy- However" for Certam Purposes as 1n t Preparatlon drochloride crystals from a butanol-water-lower alkoxy of topical orntments such as are disclosed 1n the Burkhart 1owe1- a1kan01 solvent combination a superimgtade f et s Patent 2,640,801 it is desirable that a i chlortetracycline hydrochloride crystals are unexpectedly Punty finelypowdsref1 shiortstracychns hydrochlonds obtained which consistently pass the test for use in topisalt be used or othsrwlse Manon occurs; cal ointments with the rating of II and in many instances One of the commonlyused tests for irritation is the with a Superior rating f rabbit mtradsrmal ini'tatwn test- This test 1s a quah The present invention follows the procedure set forth tative test where two reference preparations are used, a in the Winterbottom et ah patent The resulting ehlor. or non'irritafing standard and a bad or irritatmg tetracycline hydrochloride salt is then redissolved in a lower-alkoxy lower-alkanol solvent-water mixture by the Rabblts of medmm welght Preferably chmchlnas Wlth use of a nitrogenous base. Any of the nitrogenous bases skins of medium thickness and without undue vascularity Such as triethylamine, f example, Specified in the are The day before s h entire abdominal E terbottom et al. patent may be used. Suitable lower-alface is clipped with an electric cl1pper. Just prior to mkoxy lower alkanol solvents are 2 metheXyethanoh 2- jection, the rabbits are anssthstized Wlth Sodium Panto 40 ethoxyethanol, etc. The insoluble impurities are then rebarbital injected in the ear vein. A 0.5 percent test solumoved by filtration and the separated insoluhles are tion of each sample of chlortetracycline hydrochloride is washed with butanoh for example, nghutanoh The 51- P t i b dissolving 50 mluigrjallls of the compound In trate and wash liquid are combined and hydrochloric acid 10 mlnlhters of Pymgen'free dlsuued Water; standard is added thereto to induce crystallization and precipitaand s samples Prepared F same tion of the purified chlortetracycline as a hydrochloride In all Cases gowns shakmg for one minute or salt. The chlortetracycline hydrochloride is thereafter longer f 1 necessary washed and dried in the usual manner to obtain a high one'mlnlhter turPerculm synnges fitted Wlth yield of a therapeutically elfective and acceptable product. 27-gauge needles with intradermal bevels are used. 0.1 The proportionsof lowehalkexy lewehalkanel solvent, milliliter of each of the four solutions (good standard, water and butanal may vary within rather narrow i i bad siandard and F w test Samples) are injected as Preferably, the recrystallizing solution consists of 20- supenficially as poss ble, ust laterally to the mammary 35% mbutanol, water and 2 ethOXy glands Outslde mp1?1e and not m Pmxlmlty to the ethanol. The pH of this solution is preferably adjusted movable skin P t fore and hind s A Separate to a pH of between 0.5 to 2.5 With hydrochloric acid to needle and synnge used for each Solutlon' The precipitate purified crystals of chlortetracycline hydrotern of injection in each rabbit is as follows: chloride.

HEAD The invention will be described in greater detail in conjunction with the following specific examples. Bad Standard -0 0 Bad Standard XAM Test Solution -0 0- Test Solution E PLE 1 2 N 1 Recrystallization of crude chlortetracyclme hydrochlorrde Standard 0 standard An 85 kilogram portion of crude product, assaying (TAIL) 880 mcg. of chlortetracyline hydrochloride per milligram, was slurried in 451 liters of the second recrystallization The results are determined 16 to 20 our after injecmother liquor from a previous batch. The composition tion. A value of 1.0 is assigned to the good standard, of this mother liquor was 21% n-butanol, 22% distilled and a value of 4.0 is assigned to the bad standard. The water, and 57% 2-ethoxyethanol. The slurry was chilled reaction of the rabbits to the test solutions are compared to 4 C. and the chlortetracycline hydrochloride was to the standards and are assigned values between 1.0 and caused to dissolve by adding 2 moles of triethylamine per 4.0. The values obtained from three rabbits for each solution are added together and classified as follows:

1 mole of chlortetracycline based on a wet assay of the crude product. The pH of the solution was adjusted to 3 0.8 with hydrochloric acid and the solution was aged for 16 hours with continuous agitation. The crystals which formed were collected by filtration, then slurried in 203 liters of 2-ethoxyethanol and 9.75 liters of distilled water. This slurry was chilled to 2 C. and solution of the chlortetracycline hydrochloride accomplished again by the addition of triethylamine. A 1.87 kilogram quantity of activated carbon and 3.9 kilograms of Hyflo Super-Ce] were added to the solution and this sludge filtered through a sparkler filter into a tank containing 67.6 liters of distilled water. The filter cake was rinsed with 117.5 liters of n-butanol and this rinse added to the filtrate. The pH of this combined filtrate and wash was adjusted to 25:0.1 with hydrochloric acid and the solution aged ll hours with continuous agitation. The crystals were collected by filtration, and the filtrate saved for recirculation. The collected crystals were reslurried in 91.3 liters of 2-ethoxyethanol, filtered, and the filtrate discarded. The crystals were then reslurried in 97.5 liters of distilled water, the pH adjusted to 1.3 with hydrochloric acid, and aging allowed to proceed for 1 hour. The crystals of chlortetracycline hydrochloride were collected by filtration, the filtrate discarded, and the crystals dried at 60 C. in a forced hot air dryer. The product yield was 85%.

EXAMPLE 2 The procedure of the preceding example was used in the preparation of several batches of chlortetracycline hydrochloride. A like number of batches of chlortetracycline hydrochloride were prepared following the procedure of the aforesaid Winterbottom et a1. patent. The results obtained and the ratings determined by the rabbit intraderm'al irritation test are shown below.

TABLE Rating (Rabbit Skin Test) Batch N0. Batch No.

The above data clearly show products prepared according to the new method had a rating of I to 11 in all instances which means that the products are useful in any pharmaceutical preparation whereas the products prepared according to the patented process varied in ratings from II and HI and which means rejection of some of these batches for use in topical ointments.

I claim:

The process of preparing purified chlortetracycline hyrochloride which comprises dissolving crude chlortetracycline hydrochloride in a mixture of 20-35% butanol, 20-25% water and 60% 2-ethoxyethanol by the addition of triethylamine and adjusting the pH of the result ing solution to a pH of between 0.5 to 2.5 with hydrochloric acid so as to precipitate purified crystals of chlortetracycline hydrochloride therefrom.

References Cited in the file of this patent UNITED STATES PATENTS 2,671,806 Winterbottom et a1. Mar. 9, 1954 

